ERVW-1

Summary

ERVW-1 (endogenous retrovirus group W member 1, envelope, HGNC:13525) is a protein-coding gene on chromosome 7q21.2, encoding Syncytin-1 (Q9UQF0). This endogenous retroviral envelope protein has retained its original fusogenic properties and participates in trophoblast fusion and the formation of a syncytium during placenta morphogenesis. It is a selective cancer dependency (DepMap: 34.8% of cell lines).

Many different human endogenous retrovirus (HERV) families are expressed in normal placental tissue at high levels, suggesting that HERVs are functionally important in reproduction. This gene is part of an HERV provirus on chromosome 7 that has inactivating mutations in the gag and pol genes. This gene is the envelope glycoprotein gene which appears to have been selectively preserved. The gene’s protein product is expressed in the placental syncytiotrophoblast and is involved in fusion of the cytotrophoblast cells to form the syncytial layer of the placenta. The protein has the characteristics of a typical retroviral envelope protein, including a furin cleavage site that separates the surface (SU) and transmembrane (TM) proteins which form a heterodimer. Alternatively spliced transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 30816 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 1 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 34.8% of screened cell lines
• MANE Select transcript: NM_001130925

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13525
Approved symbol	ERVW-1
Name	endogenous retrovirus group W member 1, envelope
Location	7q21.2
Locus type	gene with protein product
Status	Approved
Aliases	HERV-W, HERV-W-ENV, HERVW, HERV-7q, envW
Ensembl gene	ENSG00000242950
Ensembl biotype	protein_coding
OMIM	604659
Entrez	30816

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding_CDS_not_defined, 2 protein_coding

ENST00000493463, ENST00000603053, ENST00000603252, ENST00000603704, ENST00000604270

RefSeq mRNA: 2 — MANE Select: NM_001130925 NM_001130925, NM_014590

CCDS: CCDS5626

Canonical transcript exons

ENST00000603053 — 2 exons

Exon	Start	End
ENSE00003466055	92468380	92470608
ENSE00003541191	92477382	92477946

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 97.07.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2388 / max 126.3158, expressed in 15 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84789	0.2388	15

Top tissues by expression

250 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	97.07	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.72	gold quality
buccal mucosa cell	CL:0002336	87.26	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.50	gold quality
sperm	CL:0000019	80.20	gold quality
right testis	UBERON:0004534	79.92	gold quality
left testis	UBERON:0004533	79.51	gold quality
testis	UBERON:0000473	77.75	gold quality
sural nerve	UBERON:0015488	73.60	gold quality
oocyte	CL:0000023	73.48	silver quality
colonic epithelium	UBERON:0000397	71.11	silver quality
bone marrow cell	CL:0002092	66.52	silver quality
calcaneal tendon	UBERON:0003701	65.76	gold quality
tendon of biceps brachii	UBERON:0008188	65.71	silver quality
corpus callosum	UBERON:0002336	65.66	gold quality
tendon	UBERON:0000043	65.53	gold quality
amniotic fluid	UBERON:0000173	64.68	silver quality
secondary oocyte	CL:0000655	64.15	silver quality
adrenal tissue	UBERON:0018303	61.70	gold quality
decidua	UBERON:0002450	61.59	gold quality
gastrocnemius	UBERON:0001388	60.16	gold quality
muscle of leg	UBERON:0001383	59.54	gold quality
hindlimb stylopod muscle	UBERON:0004252	58.71	gold quality
tibial artery	UBERON:0007610	58.58	gold quality
tibial nerve	UBERON:0001323	58.57	gold quality
right uterine tube	UBERON:0001302	58.56	gold quality
popliteal artery	UBERON:0002250	58.56	gold quality
body of pancreas	UBERON:0001150	58.24	gold quality
right coronary artery	UBERON:0001625	58.12	gold quality
mucosa of paranasal sinus	UBERON:0005030	57.81	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	121.30
E-ANND-3	no	4.05

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ATF1, ATF4, CAMK1, CEBPZ, DDIT3, GATA2, GATA3, GCM1, HDAC5, LRRFIP1, MYB, NFKB, RELA, SP1

miRNA regulators (miRDB)

27 targeting ERVW-1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-4774-3P	98.90	67.82	737
HSA-MIR-4742-5P	98.89	68.41	1542
HSA-MIR-629-5P	98.78	68.72	1032
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-509-3P	98.12	67.25	612
HSA-MIR-4421	97.99	64.89	701
HSA-MIR-5699-3P	97.81	65.00	861
HSA-MIR-610	96.84	67.98	905
HSA-MIR-5586-3P	95.51	67.00	805

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 34.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Env HERV-W glycoprotein mediates cell-cell fusion upon interaction with the type D mammalian retrovirus receptor. Env protein was detected in the placental syncytiotrophoblast, suggesting a physiological role during pregnancy and placenta formation. (PMID:10708449)
• contributor to normal placental architecture, especially in the fusion processes of cytotrophoblasts to syncytiotrophoblasts. the gene expression of syncytin may be altered in cases with placental dysfunction such as preeclampsia or HELLP syndrome. (PMID:11854637)
• mRNA abundance for syncytin showed stimulation by forskolin in BeWo cells (PMID:12175968)
• syncytin-mediated trophoblastic fusion in human cells is regulated by GCMa (PMID:12397062)
• Syncytin gene activation is highest in term placenta (PMID:12620933)
• HERV-W Env glycoprotein is directly involved in the differentiation of primary cultures of human villous cytotrophoblasts (PMID:12724415)
• Hypoxia alters expression and function of syncytin and its receptor during trophoblast cell fusion of human placental BeWo cells: implications for impaired trophoblast syncytialisation in pre-eclampsia. (PMID:12757936)
• Syncytin gene expression is down-regulated by hypoxia, which strengthens the hypothesis that syncytin is reduced in disturbed pregnancies in the course of placental hypoxia. (PMID:14520239)
• syncytin promoter is located in the 5’ long terminal repeat (LTR) of the HERV-W gene and that binding sites for CBF and Oct in the proximal promoter are critical for transcriptional regulation of the gene in trophoblast cells. (PMID:14613893)
• relative L1 and HERV-W expression levels are elevated in representative samples of malignant vs. non-malignant ovarian tissues (PMID:15109395)
• Comparison of orthologous and paralogous (H)ERV-W elements demonstrated the selective preservation of the env gene of the ERVWE1 locus and identified specific traits underlying the process of evolution from a retroviral envelope toward a cellular gene (PMID:15254254)
• Cytoplasmic domain of syncytin is not essential for syncytin-mediated fusion but may play regulatory role. Intramolecular interaction between two heptad repeat regions (HRA and B) is involved in fusion process. (PMID:15269105)
• Syncytin’s proinflammatory properties in the nervous system demonstrate a novel role for an endogenous retrovirus protein, which may be a target for therapeutic intervention. (PMID:15452578)
• control of env ERVWE1 placental expression in hominidae by the ERVWE1 retroviral LTR and a cellular trophoblast-specific-enhancer (PMID:15507602)
• identification of the maturation requirements for env ERVWE1 fusion competence (PMID:15827173)
• The 146-bp region of the 5’-flanking region (nt-294/-148) of the human syncytin gene acts as a placenta-specific enhancer. (PMID:15888734)
• GCMa-driven syncytin expression is the key mechanism for syncytiotrophoblast formation (PMID:16004993)
• Preservation in Hominoids of a genomic structure consisting in the juxtaposition of a retrotransposon-derived MaLR LTR (enhancer in hominidae) and the ERVWE1 provirus (promoter) (PMID:16176588)
• Syncytin transcripts were found in first-trimester trophoblast cells with both villous and extravillous phenotypes and also in the JAR and JEG-3 choriocarcinoma cell lines. (PMID:16760410)
• evaluation of the interaction of the HERV-W envelope with the hASCT2 receptor; a region consisting of the N-terminal 124 amino acids of the mature glycoprotein surface subunit was determined as the minimal receptor-binding domain (PMID:16820059)
• Syncytin is expressed by human cancer cells and is involved in cancer-endothelial cell fusions (PMID:16871371)
• Median viral RNA levels for syncytin-1 were higher in brains of MS patients relative to non-MS patients and median syncytin-1 DNA levels in MS brains were higher than non-MS brain tissue. (PMID:17209768)
• Transcripts from the HERV-W element on chromosome 7q21.2 encoding syncytin and from the SOD1 gene were detected at elevated levels in biopsies from the most affected muscles from MND patients compared to biopsies from control individuals. (PMID:17453631)
• present evidence in support of the direct role for syncytin-A in mouse trophoblast stem cell fusion and differentiation involved in placental dev. (PMID:17762178)
• findings show that in both humans and mice, one of the two syncytins (human syncytin-2 and mouse syncytin-B) is immunosuppressive and, rather unexpectedly, the other (human syncytin-1 and mouse syncytin-A) is not (PMID:18077339)
• Syncytins may represent universal fusogens in primates and rodents. (PMID:18351375)
• data support the premise that the expression of GCMa and syncytin-1 precedes syncytialization of trophoblasts, e.g. at 6% O(2), which is assumed to resemble physiological conditions. (PMID:19321927)
• increased syncytin expression is associated with decreased overall survival in rectal but not in colonic cancer patients (PMID:19327884)
• Role of HERV-W syncytin-1 in placentation and maintenance of human pregnancy. (PMID:19407656)
• ERVWE1, ERVFRDE1 and ERV3 5’LTRs were all essentially hypomethylated in cytotrophoblasts during pregnancy, but showed distinct and stage-dependent methylation profiles (PMID:19561344)
• CD9 increases GCM1 expression via the cAMP/PKA signaling pathway, resulting in the increase in ERVWE1 expression. (PMID:19692500)
• HERV-W syncytin expression apparently does not play role in endometriosis. However, it may possibly influence development of endometriosis because of increased expression in normal endometrium in endometriosis patients. (PMID:19903052)
• HERV-W env triggers brain-derived neurotrophic factor (BDNF) production in human U251 glioma cells. (PMID:20100784)
• results further highlighted the existence of a correlation between the extent of the decrease in the expression levels of both syncytins 1 and 2 fusogenic proteins and the degree of severity of preeclampsia symptoms (PMID:21493955)
• Analysis of non-spliced ERVWE1 mRNAs and env mRNAs detected efficient splicing of endogenously expressed RNAs in trophoblastic but not in non-placental cells. (PMID:21771862)
• Data show that beta-catenin/BCL9-Like (BCL9L)/T-cell factor 4 (TCF4) signalling directly targets the GCM1/syncytin pathway and thereby regulates the fusion of human choriocarcinoma cells. (PMID:22109522)
• The findings suggested that syncytin 1 is shed from the placenta into the maternal circulation in association with placental microvesicles, and modulates immune cell activation and the responses of immune cells to lipopolysaccharide stimulation. (PMID:22348442)
• proposed that Syncytin-1 is regulated by PPARgamma/RXRalpha signaling during placentogenesis to drive multinuclear syncytiotrophoblast layer formation and maintenance. (PMID:22573555)
• The role of syncytin-1 and Pb1 in cell-cell fusion was studied using lentiviral vectors that express short hairpin RNAs for stable knockdown of both genes. (PMID:22573740)
• Corticotropin-releasing hormone did not influence the differentiation of isolated trophoblasts into functional syncytium as determined by beta-hCG secretion, albeit inducing syncytin-1 expression. (PMID:22971074)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	BC035947	ENSMUSG00000090486
rattus_norvegicus	LOC102549747	ENSRNOG00000066616
rattus_norvegicus		ENSRNOG00000077990

Paralogs (7): ERV3-1 (ENSG00000213462), ERVMER34-1 (ENSG00000226887), ERVFRD-1 (ENSG00000244476), ERVV-2 (ENSG00000268964), ERVV-1 (ENSG00000269526), (ENSG00000293569), (ENSG00000293570)

Protein

Protein identifiers

Syncytin-1 — Q9UQF0 (reviewed: Q9UQF0)

Alternative names: Endogenous retrovirus group W member 1, Env-W, Envelope polyprotein gPr73, Enverin, HERV-7q Envelope protein, HERV-W envelope protein, HERV-W_7q21.2 provirus ancestral Env polyprotein, Syncytin

All UniProt accessions (2): D0EYG5, Q9UQF0

UniProt curated annotations — full annotation on UniProt →

Function. This endogenous retroviral envelope protein has retained its original fusogenic properties and participates in trophoblast fusion and the formation of a syncytium during placenta morphogenesis. May induce fusion through binding of SLC1A4 and SLC1A5. Endogenous envelope proteins may have kept, lost or modified their original function during evolution. Retroviral envelope proteins mediate receptor recognition and membrane fusion during early infection. The surface protein (SU) mediates receptor recognition, while the transmembrane protein (TM) acts as a class I viral fusion protein. The protein may have at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of membranes.

Subunit / interactions. The mature envelope protein (Env) consists of a trimer of SU-TM heterodimers attached probably by a labile interchain disulfide bond. Interacts with the C-type lectin CD209/DC-SIGN. Interacts (via RBD) with SLC1A5; this interaction decreases SLC1A5 transport rate.

Subcellular location. Cell membrane Cell membrane Virion.

Tissue specificity. Expressed at higher level in placental syncytiotrophoblast. Expressed at intermediate level in testis. Seems also to be found at low level in adrenal tissue, bone marrow, breast, colon, kidney, ovary, prostate, skin, spleen, thymus, thyroid, brain and trachea. Both mRNA and protein levels are significantly increased in the brain of individuals with multiple sclerosis, particularly in astrocytes and microglia.

Post-translational modifications. Specific enzymatic cleavages in vivo yield mature proteins. Envelope glycoproteins are synthesized as an inactive precursor that is heavily N-glycosylated and processed likely by furin in the Golgi to yield the mature SU and TM proteins. The cleavage site between SU and TM requires the minimal sequence [KR]-X-[KR]-R. The intracytoplasmic tail cleavage by the viral protease that is required for the fusiogenic activity of some retroviruses envelope proteins seems to have been lost during evolution. The CXXC motif is highly conserved across a broad range of retroviral envelope proteins. It is thought to participate in the formation of a labile disulfide bond possibly with the CX6CC motif present in the transmembrane protein. Isomerization of the intersubunit disulfide bond to an SU intrachain disulfide bond is thought to occur upon receptor recognition in order to allow membrane fusion.

Domain organisation. The cytoplasmic region is essential for the fusiogenic function. The 17 amino acids long immunosuppressive region is present in many retroviral envelope proteins. Synthetic peptides derived from this relatively conserved sequence inhibit immune function in vitro and in vivo. The receptor binding domain (RBD, aa 21-142) folds into a three-stranded antiparallel beta-sheet flanked by an alpha-helix on both sides. One RBD molecule establishes multiple contacts with the transport domains of two of SLC1A5 receptor subunits. This interaction is further stabilized by the formation of a hybrid beta-sheet clamp between aa 61-66 of RBD and the beta-harpin protruding from one of the receptor subunits.

Polymorphism. All variants have fusogenic properties.

Miscellaneous. Probably involved in the development of multiple sclerosis (MS). MS is a neurodegenerative disease characterized by the gradual accumulation of focal plaques of demyelination particularly in the periventricular areas of the brain. It leads to physical and cognitive disabilities. Viral particles or intracellular RNA of HERV-W family members have been detected in tissue from patients with multiple sclerosis or schizophrenia. Orthologs in P.troglodytes, G.gorilla, P.pygmaeus and H.moloch. It can make pseudotypes with HIV-1 virions and confer infectivity. Can also induce cellular resistance to spleen necrosis virus in vitro. HERV-W family subgenomic RNAs have been observed. This provirus is intergenic, the closest flanking genes being ODAG and PEX1. The human genome contains a high percentage of proviral-like elements, also called endogenous retroviruses (ERVs) that are the genomic traces of ancient infections of the germline by exogenous retroviruses. Although most of these elements are defective, some have conserved a functional envelope (env) gene, most probably diverted by the host for its benefit.

Similarity. Belongs to the gamma type-C retroviral envelope protein family. HERV class-I W env subfamily.

RefSeq proteins (2): NP_001124397, NP_055405 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018154	TLV/ENV_coat_polyprotein	Family

Pfam: PF00429

UniProt features (52 total): glycosylation site 7, helix 7, disulfide bond 6, region of interest 5, sequence conflict 5, sequence variant 4, strand 4, chain 3, mutagenesis site 3, short sequence motif 2, topological domain 2, signal peptide 1, site 1, turn 1, transmembrane region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5HA6	X-RAY DIFFRACTION	2
6RX1	X-RAY DIFFRACTION	2.1
8OUH	ELECTRON MICROSCOPY	2.62
8OUJ	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UQF0-F1	59.55	0.03

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 317–318 (cleavage)

Disulfide bonds (6): 25–79, 27–105, 72–96, 186–405, 186–189, 397–404

Glycosylation sites (7): 169, 208, 214, 234, 242, 281, 409

Mutagenesis-validated functional residues (3):

Position	Phenotype
314–316	complete loss of cleavage between su and tm. loss of fusiogenic function.
317	complete loss of cleavage between su and tm. loss of fusiogenic function.
405	loss of fusiogenic function. no effect on cleavage between su and tm.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 31 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, BROWNE_HCMV_INFECTION_4HR_UP, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_MYOTUBE_DIFFERENTIATION, BROWNE_HCMV_INFECTION_10HR_UP, GOBP_SYNCYTIUM_FORMATION, GOBP_MYOBLAST_FUSION, GOBP_MUSCLE_CELL_DIFFERENTIATION, BROWNE_HCMV_INFECTION_14HR_UP, BROWNE_HCMV_INFECTION_48HR_UP, STAMBOLSKY_RESPONSE_TO_VITAMIN_D3_UP, JNK_DN.V1_DN, GREB1_TARGET_GENES, MIR5586_3P

GO Biological Process (4): syncytium formation by cell-cell fusion (GO:0000768), obsolete syncytium formation (GO:0006949), myoblast fusion (GO:0007520), anatomical structure morphogenesis (GO:0009653)

GO Molecular Function (0):

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell-cell fusion	1
syncytium formation by cell-cell fusion	1
myotube differentiation	1
developmental process	1
anatomical structure development	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3436 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERVW-1	CD4	P01730	996
ERVW-1	CCR5	P51681	996
ERVW-1	CXCR4	P30991	994
ERVW-1	ACE2	Q9BYF1	994
ERVW-1	ITIH4	Q14624	993
ERVW-1	SLC1A5	Q15758	989
ERVW-1	TLR4	O00206	982
ERVW-1	SLC1A4	P43007	981
ERVW-1	PLG	P00747	976
ERVW-1	CD209	Q9NNX6	975
ERVW-1	TNFRSF14	Q92956	965
ERVW-1	FN1	P02751	963
ERVW-1	MFSD2A	Q8NA29	949
ERVW-1	CFH	P08603	937
ERVW-1	CDH1	P12830	932

IntAct

3 interactions, top by confidence:

A	B	Type	Score
ERVW-1	ERVW-1	psi-mi:“MI:0407”(direct interaction)	0.440
SMC5	DKFZp686H10254	psi-mi:“MI:2364”(proximity)	0.270

ESM2 similar proteins: B6SEH8, B6SEH9, J7HBH4, O42043, O92955, P03380, P03381, P03383, P03396, P07575, P0C212, P0DTM4, P14075, P21412, P23064, P25057, P25504, P25505, P25506, P25507, P31789, P31796, P51519, P60507, P60508, P60509, P60608, P61550, P61552, P61553, P61554, P61555, P61556, P61557, P61558, P61561, P61562, P61563, P61564, Q03816

Diamond homologs: B6SEH8, B6SEH9, P03385, P03399, P04502, P08360, P11261, P11268, P11370, P15073, P31794, P31796, P60508, P60509, P61553, P61554, P61555, P61556, P61557, P61558, P61561, P61562, P61563, P61564, Q5G5D5, Q8BI41, Q9N2K0, Q9TTC0, Q9UQF0, P03380, P03381, P03383, P03386, P03387, P03388, P03390, P03391, P04027, P06445, P06752

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

423 predictions. Top by Δscore:

Variant	Effect	Δscore
7:92468944:TT:T	acceptor_gain	1.0000
7:92475174:T:TA	donor_gain	1.0000
7:92468941:CGATT:C	acceptor_gain	0.9900
7:92468944:TTCTG:T	acceptor_loss	0.9900
7:92468945:TCTGG:T	acceptor_loss	0.9900
7:92468946:C:CC	acceptor_gain	0.9900
7:92468946:C:G	acceptor_loss	0.9900
7:92468947:T:G	acceptor_loss	0.9900
7:92477378:TCA:T	donor_loss	0.9900
7:92477379:CACCA:C	donor_loss	0.9900
7:92477380:A:AC	donor_gain	0.9900
7:92477380:A:AT	donor_loss	0.9900
7:92477381:C:CC	donor_gain	0.9900
7:92477381:CCA:C	donor_gain	0.9900
7:92477381:CCACT:C	donor_gain	0.9900
7:92469049:T:TA	donor_gain	0.9800
7:92477380:AC:A	donor_gain	0.9800
7:92477381:CC:C	donor_gain	0.9800
7:92470406:T:A	donor_gain	0.9700
7:92470409:T:TA	donor_gain	0.9700
7:92475175:C:A	donor_gain	0.9600
7:92469247:C:CT	donor_gain	0.9500
7:92469248:T:TT	donor_gain	0.9500
7:92477376:A:AC	donor_gain	0.9500
7:92477377:C:CC	donor_gain	0.9500
7:92477378:TCAC:T	donor_gain	0.9500
7:92477379:CACC:C	donor_gain	0.9500
7:92477380:ACCA:A	donor_gain	0.9500
7:92477381:CCAC:C	donor_gain	0.9500
7:92468942:GATT:G	acceptor_gain	0.9400

AlphaMissense

3468 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:92470064:C:A	W106C	0.962
7:92470064:C:G	W106C	0.962
7:92469630:C:G	C251S	0.955
7:92469631:A:T	C251S	0.955
7:92469620:C:A	W254C	0.954
7:92469620:C:G	W254C	0.954
7:92469237:T:A	N382I	0.950
7:92469546:C:G	C279S	0.950
7:92469547:A:T	C279S	0.950
7:92469821:C:A	W187C	0.944
7:92469821:C:G	W187C	0.944
7:92469234:C:G	R383P	0.943
7:92469236:A:C	N382K	0.940
7:92469236:A:T	N382K	0.940
7:92469267:A:G	L372P	0.939
7:92469575:A:C	F269L	0.939
7:92469575:A:T	F269L	0.939
7:92469577:A:G	F269L	0.939
7:92470196:G:C	F62L	0.936
7:92470196:G:T	F62L	0.936
7:92470198:A:G	F62L	0.936
7:92469185:A:C	F399L	0.934
7:92469185:A:T	F399L	0.934
7:92469187:A:G	F399L	0.934
7:92470121:C:A	W87C	0.934
7:92470121:C:G	W87C	0.934
7:92469631:A:G	C251R	0.933
7:92469237:T:G	N382T	0.932
7:92469519:C:G	C288S	0.930
7:92469520:A:T	C288S	0.930

dbSNP variants (sampled 300 via entrez): RS1000442831 (7:92474858 G>A), RS1000880209 (7:92475153 G>A), RS1001182771 (7:92473451 A>C), RS1001337140 (7:92472932 A>C,G), RS1001706588 (7:92469230 T>C), RS1002035409 (7:92468113 G>A), RS1002319486 (7:92474195 A>G), RS1002345248 (7:92479522 C>G), RS1002376461 (7:92479725 A>G), RS1002629588 (7:92474500 G>A,C), RS1002831082 (7:92468221 G>A,C), RS1003022644 (7:92471178 T>C), RS1003167722 (7:92470537 A>C,G,T), RS1003230671 (7:92477508 G>A,C,T), RS1003466330 (7:92471430 A>T)

Disease associations

OMIM: gene MIM:604659 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST000175_12	Height	1.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4662944 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Human endogenous retrovirus (HERV) proteins

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
temelimab	Binding	8.66	pKd

CTD chemical–gene interactions

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Colforsin	affects cotreatment, increases expression, decreases reaction	5
Valproic Acid	affects cotreatment, increases expression, decreases reaction	5
aristolochic acid I	increases expression	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	decreases expression	1
bisphenol A	increases expression	1
perfluorooctanoic acid	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
27-hydroxycholesterol	decreases expression, decreases reaction	1
anandamide	decreases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases expression, decreases reaction	1
iodopravadoline	decreases reaction, decreases expression	1
AM 251	decreases expression, decreases reaction	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Diethylhexyl Phthalate	increases expression	1
Estradiol	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Progesterone	increases expression	1
Silicon Dioxide	decreases expression	1
Dronabinol	decreases reaction, decreases expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases expression	1
Lactic Acid	decreases expression	1
Sertraline	increases expression, affects cotreatment	1
Nanotubes, Carbon	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.